Using multiple drugs that simultaneously may prevent drug resistance and tumor regrowth

Approximately 40 percent of advanced melanoma tumors—the deadliest form of skin cancer, which can spread throughout the body—are driven to grow by the presence of BRAF mutations. New drugs called BRAF inhibitors have shown unprecedented responses as a treatment for these types of tumors, rapidly shrinking them. However, BRAF-mutated tumors frequently show early resistance to treatment and respond only partially to BRAF inhibitors, leaving behind cancer cells that lead to eventual tumor regrowth.

Translational researchers from UCLA’s Jonsson Comprehensive Cancer Center (JCCC) have published results of two back-to-back studies in the journal Cancer Discovery that provide critical insights into two key areas of how tumors resist BRAF inhibitors: the key cell-signaling pathways BRAF-mutant melanoma cells use to learn how to become resistant to inhibitor drugs, and how the limited focus of BRAF inhibitors allows melanoma cells to evolve and develop drug resistance.

The studies were published online ahead of print on November 21, 2013.

Led by Dr. Roger Lo, JCCC member and associate professor and director of the melanoma clinic in dermatology, these two studies utilized patient biopsy samples to give researchers powerful information that can be translated directly into the clinic, specifically to improve the use of BRAF inhibitor drugs in combination with other potential drugs for melanoma patients.

In the first study, Dr. Lo and colleagues discovered how tumor cells escaped the effects of BRAF inhibitors, based on the outgrowth of melanoma cells that had learned from different cell-signaling pathways how to become BRAF-inhibitor resistant. This work was based on the analysis of 100 biopsies from patients treated with BRAF inhibitors, and it highlights that BRAF inhibitor-resistant tumors use a variety of different signaling routes to learn resistance. Remarkably, a single patient could have more than one of these resistance routes.

As doctors learn what these mechanisms of tumor resistance are, they can combine inhibitor drugs that block multiple resistance routes and eventually make the tumors shrink for much longer, or go away completely.

“By helping us understand the core resistance pathways and tumor heterogeneity, fitness and mutational patterns that emerge under drug selection.” Lo said. “This study lays a foundation for clinical trials to investigate the mechanisms of tumor progression in these melanoma patients.”

The second study, also led by Lo, found that as soon as melanomas face BRAF inhibitors they are able to quickly turn on drug resistance pathways (a process called early adaptive resistance). Over time, these early adaptive resistance pathways are further fortified, allowing the tumor cells to break free of the BRAF inhibitor and resume growth. Therefore, early and late resistance processes are linked and the endgames can be quite similar although the means or mechanisms to these ends may be different. Discovering the common denominator or core melanoma escape pathways is an important conceptual advance when fighting BRAF inhibitor resistance.

“We now have a landscape view of how melanoma first adapts and then finds ways to overcome what is initially a very effective treatment” said Antoni Ribas, JCCC member and professor of medicine co-investigator in these articles. “We have already incorporated this knowledge to the testing of new combination treatments in patients to get us back ahead of melanoma and not allow it to escape.”

This work represents an international collaboration led by Dr. Lo, which includes scientists from Vanderbilt University in Nashville, Tennessee, the Melanoma Institute of Australia in Sydney, Australia, and the Ludwig Institute for Cancer Research in Brussels, Belgium.

These studies highlight the work of UCLA’s translational physician-scientists who are taking laboratory discoveries to cancer patients as quickly as possible.

This research is supported by Stand Up To Cancer, the National Cancer Institute, Burroughs Wellcome Fund, American Skin Association, Melanoma Research Alliance, Sidney Kimmel Foundation for Cancer Research, Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Ian Copeland Melanoma Fund, the Harry J. Lloyd Charitable Trust, and the National Center for Advancing Translational Sciences UCLA Clinical Translational Science Institute, The Seaver Institute, the Wesley Coyle Memorial Fund, Louis Belley and Richard Schnarr Fund, Dr. Robert Vigen Memorial Fund, the Ruby Family Foundation, the Association of American Cancer Institutes, National Health and Medical Research Council of Australia and Translational Research Program of the Cancer Institute New South Wales, and American Cancer Society Melanoma Research Professorship.

UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2013, the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 14 consecutive years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.